A. TASK AREA 1 (CLIN 0001)- YEARLY OPERATION AND MAINTENANCE OF THE REPOSITORY 1. Store and maintain the NIH Small Molecule Repository Collection a. Storage (1) The Contractor shall provide all the necessary expertise, equipment, and facilities to store, maintain, and track the Small Molecule Repository inventory.. (2) The Contractor shall provide a compound tracking and retrieval system suitable for long-term storage of a collection of small molecule compounds, both neat and in solution. The Contractor shall store samples and plates under temperature and atmospheric conditions shown to maintain compound integrity (e.g., at subambient temperatures and under dry inert gas). (3) Storage space must be sufficient to accommodate the current SMR collection of 380,000 compounds, with each compound stored in both neat form and as a DMSO solution, as well as storage capacity for compound plates to maintain a sufficient inventory of pre-plated sets for distribution and provide short-term storage of custom orders. In addition, the Contractor shall have the capacity or the expansion capability to provide storage for newly acquired compounds. It is anticipated that the SMR may ultimately contain up to 650,000 compounds. (4) The Contractor shall provide dry storage of compounds in vials (typically less than 30mg of each compound). From these dry stores, compounds shall be weighed, solubilized, and stored in solution in DMSO. Stored compounds shall be organized in a manner to optimally support the screening needs of the user community (e.g., by chemical class or target, by date of acceptance into the collection, etc.). The preferred storage method for solubilized samples is in microtubes, with a storage and retrieval system allowing for rapid and efficient cherry picking of compounds for the creation of plates. Alternative systems allowing comparable speed and efficiency of compound selection are also acceptable. The SMR collection currently contains -380,000 compounds, which are being stored in the following format: 412,000 neat samples in 4mL glass vials 470,000 samples solubilized in DMSO in .75mL Matrix tubes (5) Storage and handling shall comply with all applicable local, state and Federal regulations. b. Quality Control and Assurance (1) Quality Controi(QC) i. The Contractor shall have the ability to perform rapid analyses of weight, solubility (including filtration or centrifugation), and chemical identity and purity (e.g., LC/MS, HPLC, and/or NMR) in order to monitor the stability of compounds in the repository. The Contractor shall assess the quality of all new and re-supply compounds acquired for inclusion in the collection. In addition, the Contractor shall conduct regular monitoring of the identity and purity of compounds in the collection, through quality control analysis of a subset of collection at set intervals, as well as samples accessed for distribution. ii. Quality control capacity should be sufficient to accommodate analysis of all incoming compounds (up to 50,000 compounds per year), at least 10% of the stored collection, and all samples accessed for cherry picking. (2) Quality Assurance The Contractor shall provide adequate quality assurance to regularly monitor the fidelity of the proposed compound plating and handling processes, as well as the functioning of all equipment used to store and process the SMR c. Inventory Monitoring and Re-supply (1) Inventory Monitoring The Contractor shall monitor the compound inventory regularly to ensure that sufficient threshold quantities, as specified by the COR, of all compounds are available to support screening needs. The Contractor shall provide a plan for efficient assessment and replenishment of the library to minimize unavailable samples. (2) Replenishment of solubilized samples As solubilized samples become depleted, the Contractor shall undertake all activities necessary to replenish the sample from the neat sample inventory. The Contractor shall provide a plan for minimizing the number of samples unavailable for plating at any given time. (3) Resupply As compounds become depleted from the neat inventory, the Contractor shall undertake all activities necessary to maintain sufficient quantities of the compound inventory. d. Disaster Recovery The Contractor shall have in place a sufficient disaster recovery plan for maintaining and distributing the collection after a catastrophic event. This should include plans for off-site storage of a complete copy of the SMR compound collection, in sufficient quantities to maintain minimal operations for up to one year after any catastrophic event, as well as a plan for quickly restoring operational capabilities to a level sufficient to support minimal operations, and a longer-term plan for restoring the SMR to fully operational status. In the unlikely event of a catastrophic loss of compounds, not due to the fault or negligence of the Contractor, a separate task order may be issued to restore the collection. Compound loss due to fault or negligence of the Contractor shall be the responsibility of the Contractor and any replacement shall not be funded by the Government. 2. Compound Plating and Distribution The Contractor shall provide all the necessary expertise and equipment to meet the ongoing plating requirements detailed below. The Contractor shall have the capability of plating compounds in multiple plate types, well-arrangements, volumes, and concentrations, depending upon the requirements of the requesting screening center. Specific formats to be offered will be determined after award (see Appendix for list of formats currently in use by the SMR). a. NIH The Contractor shall provide regular and ongoing plating and distribution services for 4 high-throughput screening centers supported by the NIH through initiatives such as the MLP (see www.mli.nih.gov). Plating requirements include: (1) Full Set The Contractor shall provide automated plating of the full set of compounds contained in the SMR (including collection increases), dissolved in DMSO, in 384 and 1536 well format, to produce arrays suitable for use as mother-plates to support screening of multiple assays or as single use/assay-ready plates. It is anticipated that full set plating and distribution will be done on an annual basis, with quarterly shipments of newly acquired compounds. (2) Standard Subsets The Contractor shall have the capability of plating pre-selected subsets of the library, which will be created in collaboration with NIH and external consultants selected by NIH (see3b 'Creation of Subsets' below). It is anticipated that subset plating will be done on an annual basis and each center will be provided a copy of each subset. (3) Custom Subsets The Contractor shall have the capability of creating and plating custom subsets of the library. The Contractor may receive compound lists from the Centers, specifying the members of a custom subset, or may be given general parameters and asked to select compounds for inclusion in the subset. (4) Hit Follow-Up Cherry- Picks The Contractor shall provide rapid cherry picking to support hit verification and follow-up. Cherry pick requirements will typically range from 250-4,000 compounds per request, and limits on formats and compound number and quantity will be set by the NIH, and may be requested in single concentration or dose-response format. Turn-around times of 3-5 business days are expected. b. Fee-for-service Users In addition to providing plating and distribution of the SMR to NIH screening initiatives as described above, the Contractor shall conduct plating and distribution of the collection, on a fee-for-service basis, for NIH approved investigators. Credits will be provided on subsequent invoices which will offset contract costs. The Contractor's price for the services provided will be based on the actual costs of plating to include compound acquisition costs, labor, consumables, and indirect costs. The price may not include profit. Costs shall be monitored periodically and the prices adjusted as necessary. Plating requirements for fee-for-service users include: (1) Full Set The Contractor shall conduct automated plating of the full set of compounds contained in the SMR, suspended in DMSO, in 96, 384, and 1536 well format, to provide arrays in a format suitable for use as mother-plates to support screening of multiple assays or single use/assay-ready plates. (2) Standard Subsets The Contractor shall provide plating of pre-selected subsets of the library, typically in single-use format. These subsets will be provided in collaboration with NIH and external consultants selected by NIH (see 3b, 'Subsets' below), and may include the NIH Clinical Collection, a known bioactive set, a natural product set, diversity sets, and targeted libraries. It is anticipated that the user group for these subsets of the SMR will be substantial; therefore the Contractor shall propose a plan to provide for efficient, rapid, and cost-effective pre-selected subsets of the collection in a limited number of formats and arrangements, without significant negative impact on the plating and distribution activities to support the NIH/ Centers. (3) Custom Subsets The Contractor shall provide for custom subsets of the library. Fee-for-service custom requests will be required to specify the compounds for inclusion in the set. (4) Hit Follow-Up Cherry Picks The Contractor shall provide fee-for-service cherry picking to support hit verification. Cherry pick requests will typically range from 250-4000 compounds, and limits on formats and compound number and quantity will be set by the NIH. A standard turn-around time of 5-10 business days is considered optimal; however, this may be modified to limit impact on turn-around times for NIH/MLP orders. Prices for the fee-for-service work shall be based on actual cost of cherry picking to support hit verification.. No profit or fee can be included in the approved price(s). Costs associated with additional project management, informatics, or infrastructure required to conduct this work will not be included in the fee-for service price(s) and should be included in the proposed Task 1 budget. c. Plating Formats The Contractor shall have the ability to provide compound arrays in multiple formats. This will include multi-use plates (suitable for use as mother plates to support screening of multiple assays), single-use plates (low volume, intended for a single transfer to the assay plate), and dose-response plates (containing multiple concentrations of each compound). The Contractor shall have the ability to add new plate types and formats, as needed, at the direction of the COR. The Contractor shall have the ability to provide accurate dispensation and distribution of dry samples, in quantities and formats to be determined by the NIH (typically milligram quantities in pre-tared vials). d. Shipping The Contractor shall provide compound arrays to NIH approved requestors, as needed. It is anticipated that this will involve regular shipments with the capability to ship on a daily basis. The Contractor shall have the capability of 'next business day' shipment or mix of 'same day' and 'next business day' for domestic shipments. The Contractor should also have the capability to ship internationally. Compound shipments shall be made in such a way as to ensure the integrity of the arrays and shall comply with all applicable federal, state, and local regulations and international shipping and custom regulations. 3. Library Enhancement a. Library Assessment (with NIH and external consultants) The Contractor shall provide the necessary equipment and expertise to assess the SMR collection in order to provide recommendations for library enhancement, including, but not limited to, identifying compounds to be discarded or removed from the standard screening deck (due to promiscuous activity, problematic substructures, etc.) and areas of the library to target for expansion. The Contractor will be an active participant in library assessment activities, which will be conducted in collaboration with the NIH and external consultants identified by the NIH. b. Subsets The Contractor shall be an active participant in the recommendation of subsets of the SMR collection, in collaboration with the NIH and external consultants. Using publicly available screening data generated on the current collection, as well as their internal cheminformatic resources, the Contractor shall assist in the identification of compounds for inclusion in target and diversity-based subsets, as well as the identification of compounds for acquisition to optimize a subset. Subsets of interest may include, but are not limited to, diversity sets of varying size, a drug-like set, known bioactives, and targeted libraries for common screening targets (e.g., GPCRs, kinases, nuclear hormone receptors, and protein-protein interactions). 4. Data Management a. Compound Registration Compound structure database - The Contractor shall maintain and update an electronic database containing each chemical structure and associated chemical data, and assign a unique identifier to each unique structure. This unique identifier will provide a mechanism that may be used to map all subsequently collected data (in vitro, in vivo, in silica, etc) back to the structure. The Contractor will eliminate redundant and ambiguous chemical structures in the compound structure database. Specifically: i. Salts: each salt of a given structure will be treated as a unique structure ii. Hydrates: each hydrate of a given structure will be treated as a unique structure iii. Geometrical: each geometrical (e.g. double bond) isomer will be treated as a unique structure iv. Diastereomers: each diastereomer of a given structure will be treated as a unique structure v. Optical isomers; each enantiomer of a given structure will be treated as a unique structure vi. Isomeric ambiguity: Identical structures of unknown stereochemistry will be treated as a single unique structure. vii. Mixtures: different compositions will be treated as a unique mixture The Contractor will also maintain a list of alternative IDs associated with each structure (e.g. PubChem CID and SID, compound supplier ID, CAS number, etc.). In addition to structural information, the database should include related chemistry data including molecular weight, molecular formula, SMILES strings, IUPAC name, common names, physical properties, physical appearance, solubility, optimal storage conditions, QC data and any available material data safety information. b. Inventory and Distribution Database The Contractor shall maintain and update a compound inventory database that will record information about all samples that are, or have been, stored in the repository. Each sample will be given a unique sample identifier. The source, including supplier and lot ID, will be recorded for each physical sample that is processed through the repository. The Contractor will also maintain all information relevant to that sample such as sample specific physical properties, date of purchase or synthesis, date of quality control analysis and results, amount in stock, physical appearance, and physical constants. The database shall contain all details of each compound's plating and shipping history. These details will include such items as the structure and sample identifier, shipping date, destination, and purpose for each shipment. c. Web-based ordering and reporting System (1) The Contractor shall make available a web-based ordering system, allowing NIH-approved users to select compounds and compound sets and acceptable format and plate-type options, and in addition enable web-based reporting functionality for NIH and approved users to generate standard reports. Reports shall include, but are not limited to: Results from quality control analyses Compound submissions by date and supplier Shipment history (e.g., requestor, content of request, date request is received, shipment date) Non-commercial supplier reports, including automated emails notifying suppliers of key results Turn-around time for plating, distribution, compound-inprocessing, etc. (3) The Contractor must comply with the Electronic and Information Technology Accessibility Provisions set forth by the Architectural and Transportation Barriers Compliance Board (also referred to as the Access Board) in 36 CFR part 1194 for all electronic and information technology (EIT) products and services acquired, maintained, or used under this contract/order, including EIT deliverables such as electronic documents and reports. d. Distribution of Data Files For all shipments from the SMR, the Contractor will provide SD format data files containing, at minimum, the following information for each compound in the shipment: Chemical Structure SMILES representation lnChi Structure ID Sample ID PubChem SID Other NIH-specified identifiers, as needed Molecular Formula Molecular Weight Sample Supplier Supplier ID (structure and sample) Sample purity Storage tube barcode Plate Barcode Well location Solvent used Concentration Volume Plating Date Known Hazards Controlled substance designation (if applicable) Physicochemical Properties (calculated) Additional data elements may be added based on user feedback. e. Data Deposition It is expected that the Small Molecule Repository will deposit data on the majority of the compounds held in the collection to one or more publicly accessible databases (e.g., PubChem) designated by the NIH. Potential data exchange requirements would include, but are not limited to the following: i. For new samples, promptly submit chemical structure and descriptive information to PubChem or other NIH specified database. ii. Coordinate with NCBI or other NIH-specified database operator as necessary to validate bulk deposition procedures using one or more formats supported by that database(s). iii. As part of the data submission, provide a link to the repository web site indicating availability of that compound. This will be displayed by the database(s) as a link-out to the Repository. iv. Maintain links to PubChem and/or other NIH-specified database. If chemical structure or descriptions are revised, submit a revised entry using the previously assigned accession code. If repository web sites change, submit revised link-out data. f. Anonymized Samples It is anticipated that a subset of compounds acquired by or submitted to the SMR may be proprietary. The Contractor shall have the capability of accepting and handling anonymized samples, submitted with identifiers, but without structural information. g. Informatics Support The Contractor shall provide all informatics infrastructure and expertise to conduct all required contract activities. h. Disaster Recovery The Contractor shall have a suitable data disaster recovery plan in place, to ensure minimal loss of data and operational downtime after a catastrophic event. i. Website (1) The Contractor shall provideand maintain a Molecular Libraries Repository website, describing the SMR program, includinga description of available services and how those services can be accessed. All databases provided with contract funds shall be the property of the Federal Government. All IT systems and procedures must conform to the NIH IT Security policies and procedures. (2) The Contractor must comply with the Electronic and Information Technology Accessibility Provisions set forth by the Architectural and Transportation Barriers Compliance Board (also referred to as the Access Board) in 36 CFR part 1194 for all electronic and information technology (EIT) products and services acquired, maintained, or used under this contract/order, including EIT deliverables such as electronic documents and reports. j. Travel The Contractor will be expected to participate in meetings of the NIH Molecular Libraries Probe Production Network Steering Committee, held 3 times per year. Additional travel to advertise the program, present SMR-related data at scientific meetings, or interact with the NIH or SMR customers may be required. If required, specifics will be included in the TORFP.